Field of the Invention
Embodiments of the present invention generally relate to thromboresistant coatings for medical devices, such as intravascular glucose sensors, having a blood-contacting surface, as well as to methods for forming such coatings, and to the medical devices thus formed.
Description of the Related Art
Achieving glycemic control is facilitated by continuous or nearly continuous monitoring of patient blood glucose levels. One method for accomplishing such monitoring is through the use of an implanted glucose sensor. For example, an optical glucose sensor, such as those disclosed in U.S. Pat. Nos. 5,137,033, 5,512,246, 5,503,770, 6,627,177, 7,417,164 and 7,470,420, and U.S. Patent Publ. Nos. 2006/0083688, 2008/0188722, 2008/0188725, 2008/0187655, 2008/0305009, 2009/0018426, 2009/0018418, and co-pending U.S. patent application Ser. Nos. 11/296,898, 12/187,248, 12/172,059, 12/274,617 and 61/045,887 (each of which is incorporated herein in its entirety by reference thereto), can be deployed in the vascular system of the patient, with glucose readings taken continuously, or as needed. Of course, any indwelling intravascular glucose sensor can potentially be used in monitoring glucose for the purpose of achieving glycemic control.
The presence of foreign bodies in the vascular system of patients, such as intravascular glucose sensors, can lead to the formation of a blood clot or thrombus around the sensor. In some cases, the thrombus can result in the restriction of blood flow through the blood vessel, impairing functionality of the sensor and/or health of the patient. In some cases, the thrombus can break off and travel through the bloodstream to other parts of the body, such as the heart or brain, leading to severe health problems. As result, it is desirable to minimize the formation of a thrombus on or near the sensor.
Heparin has been used clinically for decades as an intravenous anticoagulant to treat clotting disorders and to prevent thrombus formation during surgery and interventional procedures. Coating the outer surface of a medical device, e.g., stents, prostheses, catheters, tubing, and blood storage vessels, with heparin or a heparin containing complex (See, e.g., U.S. Reissued Pat. No. RE39,438 to Shah, et al.) may reduce the thrombogenecity of the device when it comes into contact with blood by: (1) inhibiting enzymes critical to the formation of fibrin (which holds thrombi together); (2) reducing the adsorption of blood proteins, which may lead to undesirable reactions on the device surface; and (3) reducing the adhesion and activation of platelets, which play an important role in thrombogenesis. Ideally, the heparin coating substantially shields the blood from the underlying surface of the medical device, such that the blood components contact the heparin coating rather than the device surface, thus reducing the formation of thrombi or emboli (blood clots that release and travel downstream).
Unfortunately, depending on the surface material of the device, heparin may not provide a lasting and/or contiguous thromboresistant coating. Various strategies have been implemented to enhance the integrity of the heparin coating. For example, photo-activated coupling methods can be used to covalently bind heparin to a device surface thereby extending the useful life of the coating (See e.g., Surmodics' PHOTOLINK® process at www.surmodics.com/technologies-surface-biocompatibility-heparin.html). Alternatively, for certain materials, e.g., PVC, linkers such as tridodecylmethyl ammonium chloride (TDMAC) and PEO-polyethylene oxide, among others, have been used to space the heparin molecule away from the PVC surfaces (See e.g., U.S. Pat. No. 5,441,759 to Crouther et al.). Heparin may be cross-linked to polypeptides to create a thromboresistant hydrogel with peptide-specific functionality (See e.g., U.S. Pat. No. 7,303,814 to Lamberti, et al. disclosing a wound-healing functionality). Heparin derivatives or complexes, such as heparin benzalkonium chloride (hereinafter “HBAC”), have also been applied as a thromboresistant coating for medical devices. However, HBAC has not been used with success for devices, such as intravascular analyte sensors, that require passage of the analyte in the blood through the coating. Moreover, Hsu (U.S. Pat. No. 5,047,020) disclosed use of various heparin complexes for coating blood gas sensors and noted that the benzalkonium heparin complex was unsuitable for such an intravascular sensor.
Accordingly, there is an important unmet need for a thromboresistant coating and methods for applying such a coating to an intravascular analyte sensor, and in particular, a glucose sensor.
Covalent heparin modification of polysulfone membranes has been reported for use in ex vivo hemodialysis (Li et al. 2011 Macromolec Biosci 11: 1218-1226). The process utilized atmospheric glow discharge, with ammonia and argon gas for plasma treatment of flat sheet, polysulfone (PSF) membranes, which were subsequently modified via 1-Ethyl-3-(dimethylaminopropyl) carbodiimide hydrochloride/N-Hydroxysuccinimide (EDC/NHS) binding chemistry. Others have covalently bound heparin to a polysulfone membrane surface by chloromethylating aromatic rings on the membrane and then reacting with ethylene diamine (EDA) to attach amine groups to the surface (Huang et al. 2011 Macromolec Biosci 11: 131-140).